With recent advances in biotechnology, the development of medicinal peptides or proteins has become an integral part of the pharmaceutical industry (Lee, 1986, 1988). Several therapeutic proteins have been successfully produced through recombinant DNA technology, such as human growth hormone, human insulin, .alpha.-interferon, interleukin-2, TPA, and a variety of peptide vaccines, all of which are now commercially available (Banga). As oral administration generally does not result in therapeutic responses, the parenteral route is preferred However, when administered parenterally, most peptides and proteins have an extremely short half-life in the bloodstream, typically less than 2 hours, and thus require large doses and multiple daily injections or infusions. Often, the therapeutic regimens employed require close medical supervision and are difficult for most patients to accept.
Liposomes have been proposed as a carrier for intravenously (IV) administered compounds. However, the use of liposomes for slow release of liposome-entrapped material into the bloodstream has been severely restricted by the rapid clearance of liposomes from the bloodstream by cells of the reticuloendothelial system (RES). Typically, the RES will remove 80-95% of IV injected liposomes within one hour, and effectively remove circulating liposomes from the bloodstream within of 4-6 hours.
A variety of factors which influence the rate of RES uptake of liposomes have been reported (e.g., Gregoriadis, 1974; Jonah; Gregoriadis, 1972; Juliano; Allen, 1983; Kimelberg, 1976; Richardson; Lopez-Berestein; Allen, 1981; Scherphof; Gregoriadis, 1980; Hwang; Patel, 1983; Senior, 1985; Allen, 1983; Ellens; Senior, 1982; Hwang; Ashwell; Hakomori; Karlsson; Schauer; Durocher; Greenberg; Woodruff; Czop; and Okada). Briefly, liposome size, charge, degree of lipid saturation, and surface moieties have all been implicated in liposome clearance by the RES. However, no single factor identified to date has been effective to provide long blood halflife, and more particularly, a relatively high percentage of liposomes in the bloodstream than 1 day or more after IV administration.
One factor which does favor longer liposome lifetime in the bloodstream is small liposome size, typically in the size range of small unilamellar vesicles (SUVs): 0.03-0.07 microns. However, the intravesicular volume of SUVs is quite limited, to the extent that loading SUVs with a peptides or proteins in a therapeutically effective dose range is not practical for parenteral administration.